Please wait a minute...
Protein & Cell

ISSN 1674-800X

ISSN 1674-8018(Online)

CN 11-5886/Q

Postal Subscription Code 80-984

2018 Impact Factor: 7.575

Protein Cell    2017, Vol. 8 Issue (6) : 439-445    https://doi.org/10.1007/s13238-017-0385-7
MINI-REVIEW
The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells
Qianqian Li1,2, Zewen Gao1,2, Ye Chen1,2(), Min-Xin Guan1,2
1. Division of Clinical Genetics and Genomics, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
2. Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, China
 Download: PDF(1103 KB)  
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

Mesenchymal stem cells (MSCs) are progenitors of connective tissues, which have emerged as important tools for tissue engineering due to their differentiation potential along various cell types. In recent years, accumulating evidence has suggested that the regulation of mitochondria dynamics and function is essential for successful differentiation of MSCs. In this paper, we review and provide an integrated view on the role of mitochondria in MSC differentiation. The mitochondria are maintained at a relatively low activity level inMSCs, and upon induction,mtDNAcopy number, protein levels of respiratory enzymes, the oxygen consumption rate, mRNA levels of mitochondrial biogenesis- associated genes, and intracellular ATP content are increased. The regulated level of mitochondrial ROS is found not only to influence differentiation but also to contribute to the direction determination of differentiation. Understanding the roles ofmitochondrial dynamics during MSC differentiation will facilitate the optimization of differentiation protocols by adjusting biochemical properties, such as energy production or the redox status of stem cells, and ultimately, benefit the development of new pharmacologic strategies in regenerative medicine.

Keywords mesenchymal stem cells      mitochondria      differentiation     
Corresponding Author(s): Ye Chen   
Issue Date: 05 July 2017
 Cite this article:   
Qianqian Li,Zewen Gao,Ye Chen, et al. The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells[J]. Protein Cell, 2017, 8(6): 439-445.
 URL:  
https://academic.hep.com.cn/pac/EN/10.1007/s13238-017-0385-7
https://academic.hep.com.cn/pac/EN/Y2017/V8/I6/439
1 AganiFH, PichiuleP, ChavezJC, LaMannaJC (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem275:35863–35867
https://doi.org/10.1074/jbc.M005643200
2 AkuneT, OhbaS, KamekuraS, YamaguchiM, ChungUI, KubotaN, TerauchiY, HaradaY, AzumaY, NakamuraKet al. (2004) PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Investig113:846–855
https://doi.org/10.1172/JCI200419900
3 AtashiF, ModarressiA, PepperMS (2015) The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review. Stem cells and development24:1150–1163
https://doi.org/10.1089/scd.2014.0484
4 BoyetteLB, CreaseyOA, GuzikL, LozitoT, TuanR S (2014) Human bone marrow-derived mesenchymal stem cells display enhanced clonogenicity but impaired differentiation with hypoxic preconditioning. Stem cells Transl Med3:241–254
https://doi.org/10.5966/sctm.2013-0079
5 ChenCT, ShihYR, KuoTK, LeeOK, WeiYH (2008a) Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells26:960–968
https://doi.org/10.1634/stemcells.2007-0509
6 ChenY, ShaoJZ, XiangLX, DongXJ, ZhangGR (2008b) Mesenchymal stem cells: a promising candidate in regenerative medicine. Int J Biochem Cell Biol40:815–820
https://doi.org/10.1016/j.biocel.2008.01.007
7 ChenQ, ShouP, ZhengC, JiangM, CaoG, YangQ, CaoJ, XieN, VelletriT, ZhangXet al. (2016) Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ23:1128–1139
https://doi.org/10.1038/cdd.2015.168
8 Collu-MarcheseM, ShuenM, PaulyM, SaleemA, HoodDA (2015) The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Biosci Rep35:e00221
https://doi.org/10.1042/bsr20150073
9 DenuRA, HemattiP (2016) Effects of Oxidative Stress on Mesenchymal Stem Cell Biology. Oxidative Med Cell Longev2016:2989076
https://doi.org/10.1155/2016/2989076
10 EjtehadifarM, ShamsasenjanK, MovassaghpourA, AkbarzadehlalehP, DehdilaniN, AbbasiP, MolaeipourZ, SalehM (2015) The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull5:141–149
https://doi.org/10.15171/apb.2015.021
11 ForniMF, PeloggiaJ, TrudeauK, ShirihaiO, KowaltowskiAJ (2016) Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics. Stem Cells34:743–755
https://doi.org/10.1002/stem.2248
12 GeisslerS, TextorM, KuhnischJ, KonnigD, KleinO, OdeA, PfitznerT, AdjayeJ, KasperG, DudaGN (2012) Functional comparison of chronological and in vitro aging: differential role of the cytoskeleton and mitochondria in mesenchymal stromal cells. PLoS ONE7:e52700
https://doi.org/10.1371/journal.pone.0052700
13 HeywoodHK, LeeDA (2016) Bioenergetic reprogramming of articular chondrocytes by exposure to exogenous and endogenous reactive oxygen species and its role in the anabolic response to low oxygen. J Tissue Eng Regen Med10:1–9
https://doi.org/10.1002/term.2126
14 HofmannAD, BeyerM, Krause-BuchholzU, WobusM, BornhauserM, RodelG (2012) OXPHOS supercomplexes as a hallmark of the mitochondrial phenotype of adipogenic differentiated human MSCs. PLoS ONE7:e35160
https://doi.org/10.1371/journal.pone.0035160
15 HsuYC, WuYT, YuTH, WeiYH (2016) Mitochondria in mesenchymal stem cell biology and cell therapy: From cellular differentiation to mitochondrial transfer. Semin Cell Dev Biol52:119–131
https://doi.org/10.1016/j.semcdb.2016.02.011
16 HuangPI, ChenYC, ChenLH, JuanCC, KuHH, WangST, ChiouSH, ChiouGY, ChiCW, HsuCCet al. (2011) PGC-1alpha mediates differentiation of mesenchymal stem cells to brown adipose cells. J Atheroscler Thromb18:966–980
https://doi.org/10.5551/jat.7401
17 JallaliN, RidhaH, ThrasivoulouC, ButlerP, CowenT (2007) Modulation of intracellular reactive oxygen species level in chondrocytes by IGF-1, FGF, and TGF-beta1. Connect Tissue Res48:149–158
https://doi.org/10.1080/03008200701331516
18 KandaY, HinataT, KangSW, WatanabeY (2011) Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci89:250–258
https://doi.org/10.1016/j.lfs.2011.06.007
19 KimKS, ChoiHW, YoonHE, KimIY (2010) Reactive oxygen species generated by NADPH oxidase 2 and 4 are required for chondrogenic differentiation. J Biol Chem285:40294–40302
https://doi.org/10.1074/jbc.M110.126821
20 KimM, KimC, ChoiYS, KimM, ParkC, SuhY (2012) Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: implication to age-associated bone diseases and defects. Mech Ageing Dev133:215–225
https://doi.org/10.1016/j.mad.2012.03.014
21 LambertiniE, PenolazziL, MorgantiC, LisignoliG, ZiniN, AngelozziM, BonoraM, FerroniL, PintonP, ZavanBet al. (2015) Osteogenic differentiation of human MSCs: Specific occupancy of the mitochondrial DNA by NFATc1 transcription factor. Int J Biochem Cell Biol64:212–219
https://doi.org/10.1016/j.biocel.2015.04.011
22 LeeDH, LimBS, LeeYK, YangHC (2006) Effects of hydrogen peroxide (H2O2) on alkaline phosphatase activity and matrix mineralization of odontoblast and osteoblast cell lines. Cell Biol Toxicol22:39–46
https://doi.org/10.1007/s10565-006-0018-z
23 Min-WenJC, Jun-HaoET, Shyh-ChangN (2016) Stem cell mitochondria during aging. Semin Cell Dev Biol52:110–118
https://doi.org/10.1016/j.semcdb.2016.02.005
24 MoritaK, MiyamotoT, FujitaN, KubotaY, ItoK, TakuboK, MiyamotoK, NinomiyaK, SuzukiT, IwasakiRet al. (2007) Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. J Exp Med204:1613–1623
https://doi.org/10.1084/jem.20062525
25 NuschkeA, RodriguesM, StolzDB, ChuCT, GriffithL, WellsA (2014) Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. Stem cell Res Ther5:140
https://doi.org/10.1186/scrt530
26 PanH, GuanD, LiuX, LiJ, WangL, WuJ, ZhouJ, ZhangW, RenR, ZhangWet al. (2016) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res26:190–205
https://doi.org/10.1038/cr.2016.4
27 PapandreouI, CairnsRA, FontanaL, LimAL, DenkoNC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab3:187–197
https://doi.org/10.1016/j.cmet.2006.01.012
28 ParekkadanB, MilwidJM (2010) Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng12:87–117
https://doi.org/10.1146/annurev-bioeng-070909-105309
29 PatelJJ, ButtersOR, ArnettTR (2014) PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity. Cell Biochem Funct32:368–377
https://doi.org/10.1002/cbf.3025
30 PietilaM, PalomakiS, LehtonenS, RitamoI, ValmuL, NystedtJ, LaitinenS, LeskelaHV, SormunenR, PesalaJet al. (2012) Mitochondrial function and energy metabolism in umbilical cord blood- and bone marrow-derived mesenchymal stem cells. Stem Cells Dev21:575–588
https://doi.org/10.1089/scd.2011.0023
31 QuinnKP, SridharanGV, HaydenR S, KaplanDL, LeeK, GeorgakoudiI (2013) Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation. Sci Rep3:3432
https://doi.org/10.1038/srep03432
32 Salas-VidalE, LomeliH, Castro-ObregonS, CuervoR, Escalante-AlcaldeD, CovarrubiasL (1998) Reactive oxygen species participate in the control of mouse embryonic cell death. Exp Cell Res238:136–147
https://doi.org/10.1006/excr.1997.3828
33 Sanchez-AragoM, Garcia-BermudezJ, Martinez-ReyesI, SantacatterinaF, CuezvaJM (2013) Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. EMBO Rep14:638–644
https://doi.org/10.1038/embor.2013.72
34 SartS, SongL, LiY (2015) Controlling redox status for stem cell survival, expansion, and differentiation. Oxidative Med Cell Longev2015:105135
https://doi.org/10.1155/2015/105135
35 SavkovicV, LiH, SeonJK, HackerM, FranzS, SimonJC (2014) Mesenchymal stem cells in cartilage regeneration. Curr Stem Cell Res Ther9:469–488
https://doi.org/10.2174/1574888X09666140709111444
36 SchnabelD, Salas-VidalE, NarvaezV, Sanchez-Carbente MdelR, Hernandez-GarciaD, CuervoR, CovarrubiasL (2006) Expression and regulation of antioxidant enzymes in the developing limb support a function of ROS in interdigital cell death. Dev Biol291:291–299
https://doi.org/10.1016/j.ydbio.2005.12.023
37 SongBQ, ChiY, LiX, DuWJ, HanZB, TianJJ, LiJJ, ChenF, WuHH, HanLXet al. (2015) Inhibition of notch signaling promotes the adipogenic differentiation of mesenchymal stem cells through autophagy activation and PTEN-PI3K/AKT/mTOR pathway. Cell Physiol Biochem36:1991–2002
https://doi.org/10.1159/000430167
38 StechschulteLA, CzernikPJ, RotterZC, TausifFN, CorzoCA, MarcianoDP, AsteianA, ZhengJ, BruningJB, KameneckaTMet al. (2016) PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine10:174–184
https://doi.org/10.1016/j.ebiom.2016.06.040
39 TaharaEB, NavareteFD, KowaltowskiAJ (2009) Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med46:1283–1297
https://doi.org/10.1016/j.freeradbiomed.2009.02.008
40 TanJ, XuX, TongZ, LinJ, YuQ, LinY, KuangW (2015) Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res3:15003
https://doi.org/10.1038/boneres.2015.3
41 TormosKV, AnsoE, HamanakaRB, EisenbartJ, JosephJ, KalyanaramanB, ChandelNS (2011) Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab14:537–544
https://doi.org/10.1016/j.cmet.2011.08.007
42 Varela-ReyM, EmbadeN, ArizU, LuSC, MatoJM, Martinez-ChantarML (2009) Non-alcoholic steatohepatitis and animal models: understanding the human disease. Int J Biochem Cell Biol41:969–976
https://doi.org/10.1016/j.biocel.2008.10.027
43 WageggM, GaberT, LohanathaFL, HahneM, StrehlC, FangradtM, TranCL, SchonbeckK, HoffP, OdeAet al. (2012) Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. PLoS ONE7:e46483
https://doi.org/10.1371/journal.pone.0046483
44 WanY (2010) PPARgamma in bone homeostasis. Trends Endocrinol metab21:722–728
https://doi.org/10.1016/j.tem.2010.08.006
45 WanetA, RemacleN, NajarM, SokalE, ArnouldT, NajimiM, RenardP (2014) Mitochondrial remodeling in hepatic differentiation and dedifferentiation. Int J Biochem Cell Biol54:174–185
https://doi.org/10.1016/j.biocel.2014.07.015
46 WangW, ZhangY, LuW, LiuK (2015) Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine. PLoS ONE10:e0120629
https://doi.org/10.1371/journal.pone.0120629
47 ZhangY, MarsboomG, TothPT, RehmanJ (2013) Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. PLoS ONE8:e77077
https://doi.org/10.1371/journal.pone.0077077
[1] Ermin Li, Xiuya Li, Jie Huang, Chen Xu, Qianqian Liang, Kehan Ren, Aobing Bai, Chao Lu, Ruizhe Qian, Ning Sun. BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy[J]. Protein Cell, 2020, 11(9): 661-679.
[2] Wei Li, Wenchen Shen, Bo Zhang, Kuan Tian, Yamu Li, Lili Mu, Zhiyuan Luo, Xiaoling Zhong, Xudong Wu, Ying Liu, Yan Zhou. Long non-coding RNA LncKdm2bregulates cortical neuronal differentiation by cis-activating Kdm2b[J]. Protein Cell, 2020, 11(3): 161-186.
[3] Hua Qin, Andong Zhao. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics[J]. Protein Cell, 2020, 11(10): 707-722.
[4] Hui Cheng, Zhaofeng Zheng, Tao Cheng. New paradigms on hematopoietic stem cell differentiation[J]. Protein Cell, 2020, 11(1): 34-44.
[5] Qian Zheng, Peipei Liu, Ge Gao, Jiapei Yuan, Pengfeng Wang, Jinliang Huang, Leiming Xie, Xinping Lu, Fan Di, Tanjun Tong, Jun Chen, Zhi Lu, Jisong Guan, Geng Wang. Mitochondrion-processed TERC regulates senescence without affecting telomerase activities[J]. Protein Cell, 2019, 10(9): 631-648.
[6] Weili Liu, Ting Li, Pingzhang Wang, Wanchang Liu, Fujun Liu, Xiaoning Mo, Zhengyang Liu, Quansheng Song, Ping Lv, Guorui Ruan, Wenling Han. LRRC25 plays a key role in all-trans retinoic acid-induced granulocytic differentiation as a novel potential leukocyte differentiation antigen[J]. Protein Cell, 2018, 9(9): 785-798.
[7] Crystal A. Lee, Lih-Shen Chin, Lian Li. Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion[J]. Protein Cell, 2018, 9(8): 693-716.
[8] Cécile Apert, Paola Romagnoli, Joost P. M. van Meerwijk. IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes[J]. Protein Cell, 2018, 9(4): 322-332.
[9] Yi Yang, Han Wu, Xiangjin Kang, Yanhui Liang, Ting Lan, Tianjie Li, Tao Tan, Jiangyun Peng, Quanjun Zhang, Geng An, Yali Liu, Qian Yu, Zhenglai Ma, Ying Lian, Boon Seng Soh, Qingfeng Chen, Ping Liu, Yaoyong Chen, Xiaofang Sun, Rong Li, Xiumei Zhen, Ping Liu, Yang Yu, Xiaoping Li, Yong Fan. Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs[J]. Protein Cell, 2018, 9(3): 283-297.
[10] Peipei Liu, Jinliang Huang, Qian Zheng, Leiming Xie, Xinping Lu, Jie Jin, Geng Wang. Mammalian mitochondrial RNAs are degraded in the mitochondrial intermembrane space by RNASET2[J]. Protein Cell, 2017, 8(10): 735-749.
[11] Zhi-Dong Liu,Su Zhang,Jian-Jin Hao,Tao-Rong Xie,Jian-Sheng Kang. Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling[J]. Protein Cell, 2016, 7(9): 638-650.
[12] Juan Feng,Silin Lü,Yanhong Ding,Ming Zheng,Xian Wang. Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration[J]. Protein Cell, 2016, 7(6): 391-402.
[13] Jie Gao,Yue Ma,Hua-Lin Fu,Qian Luo,Zhen Wang,Yu-Huan Xiao,Hao Yang,Da-Xiang Cui,Wei-Lin Jin. Non-catalytic roles for TET1 protein negatively regulating neuronal differentiation through srGAP3 in neuroblastoma cells[J]. Protein Cell, 2016, 7(5): 351-361.
[14] Chao Lu,Yang Yang,Ran Zhao,Bingxuan Hua,Chen Xu,Zuoqin Yan,Ning Sun,Ruizhe Qian. Role of circadian gene Clock during differentiation of mouse pluripotent stem cells[J]. Protein Cell, 2016, 7(11): 820-832.
[15] Mengmeng Chen,Yang Li,Mengxue Yang,Xiaoping Chen,Yemeng Chen,Fan Yang,Sheng Lu,Shengyu Yao,Timothy Zhou,Jianghong Liu,Li Zhu,Sidan Du,Jane Y. Wu. A new method for quantifying mitochondrial axonal transport[J]. Protein Cell, 2016, 7(11): 804-819.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed